Abuse of opiates is a serious health problem in this country. Analysis of the action of endogenous opioids in the brain is one key to understanding the abuse of these drugs. Opioid peptides and their receptors are abundant in the hippocampus, but the physiological roles of the opioid peptides are only partially understood. There is a surprising discrepancy in endogenous opioid action between species. Endogenous opioids activate kappa opioid receptors to inhibit mossy fiber LTP in guinea pigs, whereas mu receptor activation facilitates the LTP in rats. Understanding how the endogenous opioids act differently in the two species at cellular and molecular levels will provide insight into the physiological and pathological roles of endogenous opioid systems in the brain. Toward this goal the following specific aims are proposed: l) Characterize endogenous opioid-induced opposing effects on mossy fiber LTP in the rat and guinea pig hippocampal slices; 2) Determine the neuronal mechanisms by which opioids mediate dual modulation of mossy fiber-CA3 synaptic transmission in the rat hippocampal slice; 3) Determine the specific signal pathways that link opioid receptor activation to the opposing effects on mossy fiber-CA3 synaptic transmission in the rat and guinea pig hippocampus. To achieve these aims extracellular electrophysiological recording and whole-cell voltage clamp techniques will be used. These studies are predicted to provide a better understanding of how endogenous opioid systems regulate hippocampal function which is thought to be important in learning, memory and the development of opioid dependence.